Anti-tumor effects of a novel retinoic acid metabolism blocking agent VN/14-1 in the N-methyl-N-nitrosourea-induced rat mammary carcinoma model and its effects on the uterus.

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TitleAnti-tumor effects of a novel retinoic acid metabolism blocking agent VN/14-1 in the N-methyl-N-nitrosourea-induced rat mammary carcinoma model and its effects on the uterus.
Publication TypeJournal Article
Year of Publication2012
AuthorsGoss, PE, Qi, S, Hu, H, Gediya, LK, Purushottamachar, P, Godbole, AM, Njar, VCO
JournalBreast Cancer Res Treat
Volume133
Issue1
Pagination137-44
Date Published2012 May
ISSN1573-7217
KeywordsAnimals, Antineoplastic Agents, Apoptosis, Bone Density, Carcinoma, Cell Size, Drug Screening Assays, Antitumor, Estradiol, Female, Imidazoles, Lipid Metabolism, Mammary Neoplasms, Experimental, Methylnitrosourea, Neoplasms, Hormone-Dependent, Organ Size, Ovariectomy, Rats, Rats, Sprague-Dawley, Tretinoin, Tumor Burden, Uterus
Abstract

VN/14-1 [4-(±)-(1H-Imidazol-1-yl)-(E)-retinoic acid], a novel retinoic acid metabolism blocking agent (RAMBA), works by inhibiting the breakdown of all-trans-retinoic acid. The purpose of this study was to evaluate the anti-tumor effects of VN/14-1 on the N-methyl-N-nitrosourea (MNU)-induced rat mammary carcinoma model, and peripheral organ effects on the uteri of immature ovariectomized (OVX) rats. In tumor burden experiments, after 56 days of administration of VN/14-1 5, 10, and 20 mg/kg/day, significant tumor reductions in mean tumor weight of 19.1, 34.4, and 44.3%, compared to tumors in control animals occurred. Cumulative tumor growth was also significantly slower in a dose-dependent manner in groups receiving 5, 10, and 20 mg/kg/day of VN/14-1 compared to growth rates in the control group. Tumor apoptosis was significant increases in animals treated with 5, 10, and 20 mg/kg/day of VN/14-1. In uterotrophic experiments, immature OVX rats given VN/14-1 significantly reduced uterine weight and blocked endometrial stimulation induced by unopposed β-estradiol (E2). In both rat models, adverse toxicities included weakness, anorexia, and reduction in body weight in the groups given the highest dose of 20 mg/kg/day. In summary, VN/14-1 inhibited tumor growth in the MNU-induced estrogen receptor (ER)-positive rat mammary tumor model, and antagonized the stimulatory effect of estrogens on the uterus. The studies suggest that VN/14-1 may be a useful novel therapy for ER-positive breast cancer.

DOI10.1007/s10549-011-1724-7
Alternate JournalBreast Cancer Res. Treat.
PubMed ID21842418
Grant List1R01CA12379-01A2 / CA / NCI NIH HHS / United States